New ‘liquid biopsy’ could help identify advanced breast cancer patients who would benefit from a change in treatment

A novel blood test that measures genetic changes in circulating cancer DNA could help identify patients with metastatic breast cancer who could benefit from a change of treatment, new research has found.

Researchers funded by Cancer Research UK and Breast Cancer Now at the University of Leicester and Imperial College London demonstrated that a single blood test could detect and track alterations in 13 different genes, including some of the most important drivers of breast cancer such as the ERBB2 gene (HER2).

The test also detects mutations in the ESR1 gene (oestrogen receptor), which has been linked to resistance to anti-hormone therapies such as aromatase inhibitors. Patients with this mutation could be eligible for a change of treatment to chemotherapy or other selective oestrogen receptor therapies such as fulvestrant (Faslodex).

This is the first time researchers have been able to analyse two types of acquired DNA mutation – called point mutations and copy number alterations (CNAs) – in a single blood test. However, further validation is needed to confirm its usefulness before any such test can be rolled out into the clinic.

Point mutations, which occur when the molecules that make up DNA are put together in the wrong order, can change the structure and function of the resulting protein. CNAs occur when extra copies of genes are incorporated into the DNA, and can lead to increased amounts of a particular protein. These types of mutation are both important drivers of breast cancer, and can affect how the disease responds to treatment.

In cases of breast cancer, needle biopsies are initially used to assess what type of breast cancer a patient has, but tumour DNA is not regularly monitored for any genetic changes that might occur over time. Detecting and tracking how tumours evolve could provide valuable information that could eventually be used alongside, or even instead of, current tests to inform clinicians of the most suitable treatment for patients at any particular time.

In the study, published in the journal Clinical Chemistry, the researchers – led by Dr David Guttery and Professor Jacqui Shaw at the University of Leicester – first tested the approach using cell-line models in the lab, showing that the test accurately detected all of the expected changes in the cancer DNA.

Researchers then analysed DNA in blood samples donated by 42 women with secondary breast cancer, and detected cancer-specific genetic changes in half of these women. None of these mutations were found in an additional nine healthy women tested, which confirmed that the changes were due to cancer.

The results also supported previous findings that the amount of DNA can be used to track the progression of cancer – when cancer was growing more, there were increased levels of tumour DNA in the blood.

With genetic changes detected in 50% of the women, the researchers found that in nine of the 42 women – equivalent to roughly 1 in 5 patients – information from their secondary tumour DNA could have been used to alter their treatment.

The test identified that seven of the women whose cancers were progressing had increased copies of the HER2-coding gene. Of these seven, three had been HER2-negative at their first diagnosis – and that their secondary tumours had become HER2-positive indicates that they would have been eligible for Herceptin.

In addition, six of the women with hormone-driven cancers had mutations in the ESR1 gene, which has been linked to resistance to anti-hormone treatments. The best course of treatment for patients with this mutation is still under discussion, however in future, these women could be advised to stop anti-hormone therapy in favour of chemotherapy.

Dr David Guttery, Lecturer in Cancer Early Detection at the University of Leicester, said:

“We have developed a novel blood test that can simultaneously detect somatic mutations and copy number alterations that are integral in driving the growth of breast cancer.

“By analysing blood plasma to measure for cancer-specific changes to key breast cancer genes – including the HER2 and oestrogen receptor genes – we hope this test could help doctors and patients choose the best treatment at the best time.

“This study represents proof of concept, and further validation is now needed to confirm the clinical usefulness of this test before any test could be rolled out.”

“This is an important step forward in monitoring metastatic breast cancer that brings us closer to having a useful blood test in the clinic.

“Where breast cancer has spread away from the breast, it can be very difficult to take tumour samples to assess how a patient’s treatment is working. ‘Liquid biopsies’ like this are not only less invasive, but could also give a fuller picture of the genetic changes happening in a patient’s tumour that might affect their response to treatment.

“If validated by further research, this blood test could help tell us how a patient’s secondary breast cancer is evolving. Analysing the genetic make-up of tumours could enable us to identify women who might benefit from changing their treatment, ensuring that breast cancer patients receive the most personalised therapy possible.”

“While survival for women with early breast cancer has greatly improved, the outlook for patients with advanced disease is still poor, something we urgently need to change. This early research could help achieve this.

“The researchers may have developed a way to track breast cancer as it grows, allowing doctors to act swiftly and give patients the treatments that are right for them as early as possible. On top of that, such a tailored approach could spare patients receiving drugs, and the side effects that go with them, that aren’t likely to work.

“If proven to be effective in further, larger studies, this research could help more women survive advanced breast cancer.”

Following publication of this ‘proof-of-concept’ study, the next steps will assess the utility of this ‘liquid biopsy’ in the clinic. The researchers will now analyse multiple samples from patients over a longer period of time, and investigate whether the test can effectively detect early resistance to anti-hormone therapy. By modifying and refining the panel of genetic markers, the team hope to be able to monitor changes in ESR1 and other key genes in greater detail.